1. Field of the Invention
This invention lies in the field of chromatography, and particularly the chromatographic technique known in the art as simulated moving bed chromatography (SMB).
2. Description of the Prior Art
SMB was developed to improve the performance of preparative binary separations over the separations that are achieved by traditional preparative batch chromatography. The improvement was especially sought in separations with low selectivity, i.e., those with α values of 1.1 to 2. The parameter α is the ratio of the retention factors k′ of the two compounds, where k′ is defined as
            t      R        -          t      0            t    0  in which tR is the retention time of the adsorbed species and to is the retention time of the non-adsorbed species (the mobile phase). The retention factor k′ is also the slope of the curve of the concentration of a solute adsorbed on in the stationary phase vs. its concentration in the mobile phase, and the curve itself is termed an isotherm). In SMB chromatography, the contact between the liquid phase and the solid phase is optimized, resulting in lower eluent consumption and better usage of the stationary phase, and therefore increased throughput. Enantiomers of chiral compounds are examples of binary separations that benefit from SMB chromatography; other examples will be known to those skilled in chromatography.
An effective batch-wise separation of enantiomers or of other binary mixtures that exhibit low selectivity typically requires a long column. Elution of the most retained compound from a long column requires a long period of time, however, which limits the system throughput. In packed-bed systems, long retention times require large amounts of stationary phase with the consumption of large volumes of mobile phase, and produce a high dilution of the separated species. A long column generates a high pressure drop across the bed, which in turn limits the operating flow rate in order to keep the operating pressure of the column below its prescribed maximum. Thus, while separation can be achieved in batch-wise systems, continuous systems are preferred for reasons of economy, particularly on a preparative scale.
The theory of moving bed chromatography is to optimize the use of the stationary phase by using a column configuration that places the stationary phase in a loop and effectively moves the stationary phase through the loop as the mobile phase is moving but in the opposite direction. Feed and eluent are introduced at different points in the loop, while extract (the more strongly retained component) and raffinate (the weakly retained component) are withdrawn at still further points in the loop that alternate with the introduction points of feed and eluent. This effectively creates counter-current flows of stationary and mobile phases.
Actual implementation of the moving bed theory requires a fixed bed, which in practical terms cannot be moved through an elongated column, particularly one that is circuitous in configuration, even when the “column” is actually a series of individual columns joined together to form the loop. The solution would appear to be to rotate the column itself, thereby avoiding any disturbance to the bed, while maintaining the points of introduction of feed and eluent and of withdrawal of extract and raffinate stationary, or alternatively, to hold the column and the bed stationary and rotate the points of introduction and withdrawal continuously around the column loop. With either alternative, a system strictly following the moving bed model would require that the points of introduction and of withdrawal continuously rotate relative to the column loop. This is likewise impractical.
Simulated moving bed chromatography removes all such impracticalities by using both a stationary column loop and stationary ports distributed around the loop, with each port capable of both introduction and withdrawal. The column loop is operated in stages, reconnecting the ports between each stage by switching valves to change the functions of the ports as introduction and withdrawal sites. For a selected time interval, therefore, the feed introduction, eluent introduction, extract withdrawal, and raffinate withdrawal ports will be located at distinct sites around the column loop, and for each succeeding time interval, these sites will be advanced by increments around the loop in the direction of flow of the eluent, thereby simulating a moving bed. Each port thus alternates between serving as an inlet and as an outlet, and between the two types of inlet as well as the two types of outlet. Descriptions of SMB chromatography can be found in Miller, L., et al., “Chromatographic resolution of the enantiomers of a pharmaceutical intermediate from the milligram to the kilogram scale,” J. Chromatog. A, 849(2), 309-317 (1999), Negawa, M., et al., U.S. Pat. No. 5,434,298 (issued Jul. 18, 1995); Nagamatsu, S., et al., U.S. Pat. No. 6,217,774 (issued Apr. 17, 2004); Ikeda, H., U.S. Pat. No. 6,372,127 (issued Apr. 16, 2002); Ikeda, H., et al., U.S. Pat. No. 6,533,936 (issued Mar. 18, 2003); Ohnishi, A., et al., United States Patent Application Publication No. US 2005/0054878 (published Mar. 10, 2005); Cavoy, E., et al., “Laboratory-developed simulated moving bed for chiral drug separations—Design of the system and separation of Tramadol enantiomers,” J. Chromatog. A 769, 49-57 (1997); and Chiral Separation Techniques—A Practical Approach, 3d ed., Subramanian, G., ed., Wiley-VCH Verlag GmbH & Co. KGaA, Wernheim, Germany (2007).
In applications of SMB chromatography, the column loops are formed by a series of individual columns connected in series, with the introduction/withdrawal ports located between columns. The span of packed bed between each pair of adjacent ports is typically termed a “zone,” the four ports thus separating the columns into four zones that move around the circuit as the various port functions are rotated. The zone between the eluent introduction and the extract withdrawal is typically referred to as Zone I; with Zone II being the zone between the extract withdrawal and the feed introduction, Zone III being the zone between the feed introduction and the raffinate withdrawal, and Zone IV being the zone between the raffinate withdrawal and the eluent introduction. Each zone can be occupied by as little as a single column, but most often a zone consists of two or more columns to allow the stepwise advances that are smaller distances than the length of an entire zone. This permits the system to more closely approach the model of a true moving bed (TMB), but it also allows the system to be operated with zones of different bed lengths (i.e., different numbers of columns from one zone to the next), and to be operated in an asynchronous manner (commonly known as “Varicol”), i.e., by switching different port functions at different times rather than all at the same time, or under cyclic flow modulation wherein the flow rates are allowed to change during a switching period (commonly known as “PowerFeed”).
Regardless of the operational protocol of an SMB system, the system is limited by pressure drop considerations, since the overall pressure drop includes contributions from the pressure drops in each of the four zones. Limitations on the pressure drop impose limitations on the throughput, which can present a problem when separating mixtures with high a, i.e., those in which one component is much more strongly retained by the stationary phase than the other. In batch separations, a component that is strongly retained, such as in a mixture with α>4, can be recovered by using a short column, a solvent gradient, or both, to reduce the elution time. If one were to separate the same mixture in a continuous SMB operation, the separation would require a high flow rate in Zone I. If one also sought a high rate of feed mixture through the SMB system, one would run Zones II and III at their highest possible flow rates. This would be limited however by the pressure drop in Zone I. Thus, in conventional SMB systems, separating mixtures that include a strongly retained component by running Zone I at a high pressure drop while keeping the overall pressure drop within the system limit leaves with little room for pressure drops in Zones II and III and thereby compromises the throughput rate.